Combination therapy for the treatment of tinnitus and other medical conditions

ABSTRACT

The disclosure provides for a combination therapy comprising different classes of medications for the treatment of tinnitus and other medical conditions, and methods of treatment thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119 from ProvisionalApplication Ser. No. 62/768,820, filed Nov. 16, 2018, the disclosure ofwhich is incorporated herein by reference.

TECHNICAL FIELD

The disclosure provides for a combination therapy comprising differentclasses of medications for the treatment of tinnitus and other medicalconditions, and methods of treatment thereof.

BACKGROUND

Tinnitus is the perception of sound in the absence of acousticstimulation, and often involves sound sensations such as ringing,buzzing, roaring, whistling, and hissing that cannot be attributed to anexternal sound source. Tinnitus is a symptom associated with many formsof hearing loss and can also be a symptom of other health problems. Itis estimated that more than 40 million people in the United Statesexperience chronic tinnitus and 10 million of these people considertheir tinnitus to be serious problem.

SUMMARY

There are presently no FDA-approved drugs specifically for tinnitus, andno medications that have been shown to reverse the neural hyperactivityat the root of tinnitus. The disclosure provides for combinationtherapies comprising different classes of medications that were shown tohave efficacy based upon preliminary clinical data in a retrospectiveanalysis of patients treated with the medications. More specifically itwas found that a combination of medications from different drug classesprovided beneficial or ameliorative effects in treating otologicconditions (e.g., tinnitus or vertigo) or an otologic symptom (e.g.,tinnitus or vertigo) associated with a disease or disorder (e.g.,headache or inflammatory intestinal disorder) in a subject in needthereof. For example, retrospective analysis of the preliminary clinicaldata indicated that an otologic condition or otologic symptom disclosedherein can be treated with a combined therapy of two or more drugsselected from the following drug classes: tricyclic antidepressants,anti-seizure medications, beta blockers, carbonic anhydrase inhibitors,selective serotonin reuptake inhibitors, selective norepinephrinereuptake inhibitors, calcium or sodium channel blockers, serotoninnorepinephrine reuptake inhibitors, specific serotonin antidepressants,unicyclic antidepressants, tricyclic secondary amines, tricyclictertiary amines, and antidepressants/serotonin modulators. In view ofthe improvements in primary and secondary treatment outcomes in theretrospective analysis, a large, randomized, double-blinded, placebocontrolled, single institutional 12-week study is proposed herein.

In a particular embodiment, the disclosure provides for a compositionfor the treatment of an otologic condition, or an otologic symptom(s)associated with a disease or disorder, comprising therapeuticallyeffective amounts of a first medication and a second medication selectedfrom the following drug classes: tricyclic antidepressants, anti-seizuremedications, beta blockers, carbonic anhydrase inhibitors, selectiveserotonin reuptake inhibitors, and calcium or sodium channel blockers,wherein the first medication is from a different drug class than thesecond medication. In a further embodiment, the ratio by weight of thefirst medication to the second medication in the composition is from20:1 to 1:20. In yet a further embodiment of any of the foregoingembodiments, the ratio by weight of the first medication to the secondmedication in the composition is from 10:1 to 1:10. In yet a furtherembodiment of any of the foregoing embodiments, the first medication ofthe composition is a tricyclic antidepressant; and the second medicationis selected from the group consisting of an anti-seizure medication, abeta blocker, a calcium or sodium channel blocker, and a carbonicanhydrase inhibitor. Examples of tricyclic antidepressants, include butare not limited to, amineptine, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dosulepin, doxepin, imipramine, imipraminoxide,iprindole, lofepramine, melitracen, metapramine, nitroxazepine,nortriptyline, noxiptiline, opipramol, pipofezine, propizepine,protriptyline, quinupramine, tianeptine, and trimipramine. In yet afurther embodiment of any of the foregoing embodiments, the tricyclicantidepressant is nortriptyline or amitriptyline. In yet a furtherembodiment of any of the foregoing embodiments, the compositioncomprises nortriptyline at a dose of 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg,or 125 mg, or a range that includes or is between any two of theforegoing doses. In yet a further embodiment of any of the foregoingembodiments, the composition comprises amitriptyline at a dose of 1 mg,5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105mg, 110 mg, 115 mg, 120 mg, or 125 mg, or a range that includes or isbetween any two of the foregoing doses. In yet a further embodiment ofany of the foregoing embodiments, the second medication is ananti-seizure medication selected from gabapentin and topiramate. In yeta further embodiment of any of the foregoing embodiments, the secondmedication is propranolol, a beta blocker. In yet a further embodimentof any of the foregoing embodiments, the second medication verapamil, acalcium or sodium channel blocker. In yet a further embodiment of any ofthe foregoing embodiments, the second medication is acetazolamide, acarbonic anhydrase inhibitor. In yet a further embodiment of any of theforegoing embodiments, the first medication of the composition is aselective serotonin inhibitor; and the second medication of thecomposition is selected from the group consisting of an anti-seizuremedication, a beta blocker, a sodium or calcium channel blocker, and acarbonic anhydrase inhibitor. In yet a further embodiment of any of theforegoing embodiments, the first medication is a selective serotonininhibitor selected from the group consisting of citalopram,escitalopram, fluoxetine, fluvoxamine, indalpine, paroxetine,sertraline, and zimelidine. In yet a further embodiment of any of theforegoing embodiments, the first medication is paroxetine. In yet afurther embodiment of any of the foregoing embodiments, the compositioncomprises paroxetine at a dose of 3 mg, 5 mg, 10 mg, 12 mg, 14 mg, 15mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 25 mg, 26 mg, 28 mg, 30 mg, 32mg, 34 mg, 35 mg, 36 mg, 38 mg, 40 mg, or a range that includes or isbetween any two of the foregoing doses. In yet a further embodiment ofany of the foregoing embodiments, the second medication is ananti-seizure medication selected from gabapentin and topiramate. In yeta further embodiment of any of the foregoing embodiments, the secondmedication is propranolol, a beta blocker. In yet a further embodimentof any of the foregoing embodiments, the second medication is verapamil,a calcium or sodium channel blocker. In yet a further embodiment of anyof the foregoing embodiments, the second medication is acetazolamide, acarbonic anhydrase inhibitor. In yet a further embodiment of any of theforegoing embodiments, the first medication is a calcium or sodiumchannel blocker; and the second medication is selected from the groupconsisting of a tricyclic antidepressant, an anti-seizure medication,and a carbonic anhydrase inhibitor. In yet a further embodiment of anyof the foregoing embodiments, the calcium or sodium channel blocker isselected from the group consisting of ethadione, paramethadione,trimethadione, ethosuximide, mesuximide, phensuximide, gabapentin,pregabalin, imepitoin, lamotrigine, topiramate, verapamil, andzonisamide. In yet a further embodiment of any of the foregoingembodiments, the first medication is verapamil. In yet a furtherembodiment of any of the foregoing embodiments, the compositioncomprises verapamil at a dose of 20 mg, 40 mg, 50 mg, 100 mg, 150 mg,200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg,650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 1000 mg, 1050 mg, 1100mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700mg, or a range that includes or is between any two of the foregoingdoses. In yet a further embodiment of any of the foregoing embodiments,the second medication is a tricyclic antidepressant selected fromnortriptyline and amitriptyline. In yet a further embodiment of any ofthe foregoing embodiments, the second medication is an antiseizuremedication selected from gabapentin and topiramate. In yet a furtherembodiment of any of the foregoing embodiments, the second medication isacetazolamide, a carbonic anhydrase inhibitor. In yet a furtherembodiment of any of the foregoing embodiments, the first medication ofthe composition is an anti-seizure medication; and the second medicationof the composition is selected from the group consisting of a tricyclicantidepressant, a selective serotonin inhibitor, a beta blocker, and asodium or calcium channel blocker. In yet a further embodiment of any ofthe foregoing embodiments, the anti-seizure medication is selected fromthe group consisting of acetazolamide, carbamazepine, clobazam,clonazepam, diazepam, divalproex sodium, ethosuximide, ethotoin,felbamate, fosphenytoin, gabapentin, lamotrigine, lacosamide,levetiracetam, lorazepam, mephenytoin, metharbital, methsuximide,methazolamide, nitrazepam, oxcarbazepine, phenobarbital, phenytoin,phensuximide, pregabalin, primidone, rufinamide, sodium valproate,stiripentol, tiagabine, topiramate, trimethadione, valproic acid,vigabatrin, and zonisamide. In yet a further embodiment of any of theforegoing embodiments, the first medication is gabapentin or topiramate.In yet a further embodiment of any of the foregoing embodiments, thecomposition comprises gabapentin at a dose of 40 mg, 50 mg, 100 mg, 150mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 1000 mg, 1050 mg,1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg,1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg,1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg,2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg,2700 mg, or a range that includes or is between any two of the foregoingdoses. In yet a further embodiment of any of the foregoing embodiments,the composition comprises topiramate at a dose of 7 mg, 10 mg, 15 mg, 20mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg,120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg,165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, or arange that includes or is between any two of the foregoing doses. In yeta further embodiment of any of the foregoing embodiments, the firstmedication of the composition is a carbonic anhydrase inhibitor; and thesecond medication of the composition is selected from the groupconsisting of a tricyclic antidepressant, a selective serotonininhibitor, a and a sodium or calcium channel blocker. In yet a furtherembodiment of any of the foregoing embodiments, the carbonic anhydraseinhibitor is selected from acetazolamide, dichlorphenamide, andzonisamide. In yet a further embodiment of any of the foregoingembodiments, the carbonic anhydrase inhibitor is acetazolamide. In yet afurther embodiment of any of the foregoing embodiments, the compositioncomprises acetazolamide at a dose of 60 mg, 100 mg, 150 mg, 200 mg, 250mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700mg, 750 mg, 800 mg, 850 mg, 900 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg,1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, or arange that includes or is between any two of the foregoing doses. In yeta further embodiment of any of the foregoing embodiments, the firstmedication of the composition is a beta blocker; and the secondmedication of the composition is selected from a tricyclicantidepressant and a selective serotonin reuptake inhibitor. In yet afurther embodiment of any of the foregoing embodiments, the beta blockeris selected from the group consisting of alprenolol, bopindolol,bupranolol, carteolol, cloranolol, mepindolol, nadolol, oxprenolol,penbutolol, pindolol, iodopindolol, propranolol, sotalol, tertatolol,timolol, acebutolol, atenolol, betaxolol, bevantolol, bisoprolol,celiprolol, epanolol, esmolol, landiolol, metoprolol, nebivolol,practolol, S-atenolol, talinolol, butaxamine, arotinolol, carvedilol,and labetalol. In yet a further embodiment of any of the foregoingembodiments, the beta blocker is propranolol. In yet a furtherembodiment of any of the foregoing embodiments, the compositioncomprises propranolol at a dose of 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg,130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg or a range thatincludes or is between any two of the foregoing doses. In yet a furtherembodiment of any of the foregoing embodiments, the composition is apharmaceutically acceptable composition that further comprisesexcipient(s), diluent(s) and/or carrier(s). In yet a further embodimentof any of the foregoing embodiments, the composition is formulated fororal delivery. In yet a further embodiment of any of the foregoingembodiments, the composition is in the form of a pill, tablet, orcapsule. In yet a further embodiment of any of the foregoingembodiments, the composition is formulated as a single unit dose. In yeta further embodiment of any of the foregoing embodiments, thecomposition is formulated as a multi-unit dose. In yet a furtherembodiment of any of the foregoing embodiments, the compositioncomprises a submaximal dose of the first medication and/or a submaximaldose of the second medication. In yet a further embodiment of any of theforegoing embodiments, the composition comprises less than about 75%,60%, 50%, 40%, 30%, 20%, or 10% of the maximal dose of the firstmedication and/or the second medication.

In a certain embodiment, the disclosure also provides a method oftreating an otologic condition, or an otologic symptom(s) associatedwith a disease or disorder, in a subject in need thereof, comprising:administering to the subject a combined therapy comprisingtherapeutically effective amounts of two or more medications selectedfrom the following drug classes: tricyclic antidepressants, anti-seizuremedications, beta blockers, carbonic anhydrase inhibitors, selectiveserotonin reuptake inhibitors, and calcium or sodium channel blockers,wherein the two or more medications are from different drug classes. Ina further embodiment, the otologic condition is selected from the groupconsisting of tinnitus, fluctuating or sudden hearing loss,sensorineural hearing loss, dizziness, vertigo, aural pressure/pain, andfluctuating hearing loss. In yet a further embodiment of any of theforegoing embodiments, the otologic symptom(s) associated with a diseaseor disorder comprises tinnitus and/or vertigo. In yet a furtherembodiment of any of the foregoing embodiments, the otologic symptom(s)are associated with a disease or disorder selected from the groupconsisting of neck pain, headache, irritable bowel syndrome,interstitial cystitis, migraine-related disorders, and fibromyalgia. Inyet a further embodiment of any of the foregoing embodiments, thesubject is a human patient having the otologic symptom(s) of tinnitusand/or vertigo. In yet a further embodiment of any of the foregoingembodiments, one of the medications of the combined therapy is atricyclic antidepressant selected from the group consisting ofamineptine, amitriptyline, amitriptylinoxide butriptyline, clomipramine,demexiptiline, desipramine, dibenzepin, dimetacrine, dosulepin, doxepin,imipramine, imipraminoxide, iprindole, lofepramine, melitracen,metapramine, nitroxazepine, nortriptyline, noxiptiline, opipramol,pipofezine, propizepine, protriptyline, quinupramine, tianeptine, andtrimipramine. In yet a further embodiment of any of the foregoingembodiments, the tricyclic antidepressant is nortriptyline oramitriptyline. In yet a further embodiment of any of the foregoingembodiments, nortriptyline is administered at a dose of 1 mg, 5 mg, 10mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110mg, 115 mg, 120 mg, or 125 mg, or a range that includes or is betweenany two of the foregoing doses. In yet a further embodiment of any ofthe foregoing embodiments, amitriptyline is administered at a dose of 1mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg,55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg,105 mg, 110 mg, 115 mg, 120 mg, or 125 mg, or a range that includes oris between any two of the foregoing doses. In yet a further embodimentof any of the foregoing embodiments, one of the medications of thecombined therapy is an anti-seizure medication selected from the groupconsisting of acetazolamide, carbamazepine, clobazam, clonazepam,diazepam, divalproex sodium, ethosuximide, ethotoin, felbamate,fosphenytoin, gabapentin, topiramate, lamotrigine, lacosamide,levetiracetam, lorazepam, mephenytoin, metharbital, methsuximide,methazolamide, nitrazepam, oxcarbazepine, phenobarbital, phenytoin,phensuximide, pregabalin, primidone, rufinamide, sodium valproate,stiripentol, tiagabine, trimethadione, valproic acid, vigabatrin, andzonisamide. In yet a further embodiment of any of the foregoingembodiments, the anti-seizure medication is topiramate or gabapentin. Inyet a further embodiment of any of the foregoing embodiments, topiramateis administered at a dose of 7 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, or a range that includes oris between any two of the foregoing doses. In yet a further embodimentof any of the foregoing embodiments, gabapentin is administered at adose of 40 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg,400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg,850 mg, 900 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg,1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg,1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg,2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg,2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, or a range that includes oris between any two of the foregoing doses. In yet a further embodimentof any of the foregoing embodiments, one of the medications of thecombined therapy is a beta blocker selected from the group consisting ofalprenolol, bopindolol, bupranolol, carteolol, cloranolol, mepindolol,nadolol, oxprenolol, penbutolol, pindolol, iodopindolol, propranolol,sotalol, tertatolol, timolol, acebutolol, atenolol, betaxolol,bevantolol, bisoprolol, celiprolol, epanolol, esmolol, landiolol,metoprolol, nebivolol, practolol, S-atenolol, talinolol, butaxamine,arotinolol, carvedilol, and labetalol. In yet a further embodiment ofany of the foregoing embodiments, the beta blocker is propranolol. Inyet a further embodiment of any of the foregoing embodiments,propranolol is administered at a dose of 9 mg, 10 mg, 15 mg, 20 mg, 25mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg,125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg or arange that includes or is between any two of the foregoing doses. In yeta further embodiment of any of the foregoing embodiments, one of themedications of the combined therapy is a carbonic anhydrase inhibitorselected from the group consisting of acetazolamide, dichlorphenamide,and zonisamide. In yet a further embodiment of any of the foregoingembodiments, the carbonic anhydrase inhibitor is acetazolamide. In yet afurther embodiment of any of the foregoing embodiments, acetazolamide isadministered at a dose of 60 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg,350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg,800 mg, 850 mg, 900 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg,1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, or a range thatincludes or is between any two of the foregoing doses. In yet a furtherembodiment of any of the foregoing embodiments, one of the medicationsof the combined therapy is a selective serotonin reuptake inhibitorselected from the group consisting of citalopram, escitalopram,fluoxetine, fluvoxamine, indalpine, paroxetine, sertraline, andzimelidine. In yet a further embodiment of any of the foregoingembodiments, the selective serotonin reuptake inhibitor is paroxetine.In yet a further embodiment of any of the foregoing embodiments,paroxetine is administered at a dose of 3 mg, 5 mg, 10 mg, 12 mg, 14 mg,15 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 25 mg, 26 mg, 28 mg, 30 mg, 32mg, 34 mg, 35 mg, 36 mg, 38 mg, 40 mg, or a range that includes or isbetween any two of the foregoing doses. In yet a further embodiment ofany of the foregoing embodiments, one of the medications of the combinedtherapy is a calcium or sodium channel blocker selected from the groupconsisting of ethadione, paramethadione, trimethadione, ethosuximide,mesuximide, phensuximide, gabapentin, pregabalin, imepitoin,lamotrigine, verapamil, and zonisamide. In yet a further embodiment ofany of the foregoing embodiments, the calcium or sodium channel blockeris verapamil. In yet a further embodiment of any of the foregoingembodiments, verapamil is administered at a dose of 20 mg, 40 mg, 50 mg,100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg,550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 1000 mg,1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg,1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg,1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg,2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg,2650 mg, 2700 mg, or a range that includes or is between any two of theforegoing doses. In yet a further embodiment of any of the foregoingembodiments, the combined therapy comprises nortriptyline andtopiramate; nortriptyline and gabapentin; amitriptyline and topiramate;amitriptyline and gabapentin; nortriptyline and propranolol;amitriptyline and propranolol; nortriptyline and verapamil;amitriptyline and verapamil; nortriptyline and acetazolamide;amitriptyline and acetazolamide; paroxetine and topiramate; paroxetineand gabapentin; paroxetine and propranolol; paroxetine and verapamil;paroxetine and acetazolamide; verapamil and topiramate; verapamil andgabapentin; or verapamil and acetazolamide. In yet a further embodimentof any of the foregoing embodiments, the medications of the combinedtherapy are concomitantly administered. In yet a further embodiment ofany of the foregoing embodiments, the medications of the combinedtherapy are sequentially administered. In yet a further embodiment ofany of the foregoing embodiments, the medications of the combinedtherapy are administered at submaximal doses. In yet a furtherembodiment of any of the foregoing embodiments, each medication of thecombined therapy is administered at 75%, 60%, 50%, 40%, 30%, 20%, or 10%of the maximal dose for the medication. In yet a further embodiment ofany of the foregoing embodiments, the combined therapy is prepared aspharmaceutical composition(s) formulated for oral administration. In yeta further embodiment of any of the foregoing embodiments, themedications of the combined therapy are formulated as a single unit oraldosage form for oral administration. In yet a further embodiment of anyof the foregoing embodiments, the medications of the combined therapyare formulated as multi-unit oral dosage forms for oral administration.In yet a further embodiment of any of the foregoing embodiments, thesubject has tinnitus, and the administration of the combined therapy tothe subject provides one or more of the following effects: improvementin a subject's tinnitus functional index; a decrease in the averagenumber days in which the subject has annoying tinnitus; and/or adecrease in the level of tinnitus loudness.

In a particular embodiment, the disclosure further provides acomposition for the treatment of an otologic condition, or an otologicsymptom(s) associated with a disease or disorder, comprisingtherapeutically effective amounts of a first medication and a secondmedication selected from the following drug classes: tricyclicantidepressants, anti-seizure medications, beta blockers, carbonicanhydrase inhibitors, selective serotonin reuptake inhibitors, andcalcium or sodium channel blockers, wherein the first medication is froma different drug class than the second medication. In a furtherembodiment, the first medication of the composition is a tricyclicantidepressant; and the second medication is selected from the groupconsisting of an anti-seizure medication, a beta blocker, a calcium orsodium channel blocker, and a carbonic anhydrase inhibitor. In yet afurther embodiment of any of the foregoing embodiments, the firstmedication of the composition is a selective serotonin inhibitor; andthe second medication of the composition is selected from the groupconsisting of an anti-seizure medication, a beta blocker, a sodium orcalcium channel blocker, and a carbonic anhydrase inhibitor. In yet afurther embodiment of any of the foregoing embodiments, the firstmedication is a calcium or sodium channel blocker; and the secondmedication is selected from the group consisting of a tricyclicantidepressant, an anti-seizure medication, and a carbonic anhydraseinhibitor. In yet a further embodiment of any of the foregoingembodiments, the first medication of the composition is an anti-seizuremedication; and the second medication of the composition is selectedfrom the group consisting of a tricyclic antidepressant, a selectiveserotonin inhibitor, a beta blocker, and a sodium or calcium channelblocker. In yet a further embodiment of any of the foregoingembodiments, the first medication of the composition is a carbonicanhydrase inhibitor; and the second medication of the composition isselected from the group consisting of a tricyclic antidepressant, aselective serotonin inhibitor, a and a sodium or calcium channelblocker. In yet a further embodiment of any of the foregoingembodiments, the first medication of the composition is a beta blocker;and the second medication of the composition is selected from atricyclic antidepressant and a selective serotonin reuptake inhibitor.In yet a further embodiment of any of the foregoing embodiments, thefirst medication and the second medication combinations are selectedfrom the group consisting of nortriptyline and topiramate, nortriptylineand gabapentin, amitriptyline and topiramate, amitriptyline andgabapentin, nortriptyline and propranolol, amitriptyline andpropranolol, nortriptyline and verapamil, amitriptyline and verapamil,nortriptyline and acetazolamide, amitriptyline and acetazolamide,paroxetine and topiramate, paroxetine and gabapentin, paroxetine andpropranolol, paroxetine and verapamil, paroxetine and acetazolamide,verapamil and topiramate, verapamil and gabapentin, and verapamil andacetazolamide. In yet a further embodiment of any of the foregoingembodiments, the composition is formulated for oral delivery and is inthe form of a pill, a tablet, or a capsule. In yet a further embodimentof any of the foregoing embodiments, the composition comprises less thanabout 75% of the maximal dose of the first medication and/or the secondmedication.

In a certain embodiment, the disclosure provides a method of treating anotologic condition, or an otologic symptom(s) associated with a diseaseor disorder, in a subject in need thereof, comprising: administering tothe subject a combined therapy comprising therapeutically effectiveamounts of two or more medications selected from the following drugclasses: tricyclic antidepressants, anti-seizure medications, betablockers, carbonic anhydrase inhibitors, selective serotonin reuptakeinhibitors, and calcium or sodium channel blockers, wherein the two ormore medications are from different drug classes. In a furtherembodiment, the otologic condition is selected from the group consistingof tinnitus, fluctuating or sudden hearing loss, sensorineural hearingloss, dizziness, vertigo, aural pressure/pain, and fluctuating hearingloss, and wherein the otologic symptom(s) associated with a disease ordisorder comprises tinnitus and/or vertigo. In yet a further embodimentof any of the foregoing embodiments, the subject is a human patienthaving tinnitus. In yet a further embodiment of any of the foregoingembodiments, administration of the combined therapy to the subjectprovides one or more of the following effects: improvement in asubject's tinnitus functional index; a decrease in the average numberdays in which the subject has annoying tinnitus; and/or a decrease inthe level of tinnitus loudness. In yet a further embodiment of any ofthe foregoing embodiments, combinations of the two or more medicationsof the combined therapy are selected from the group consisting of: atricyclic antidepressant and an anti-seizure medication, a tricyclicantidepressant and a beta blocker, a tricyclic antidepressant and asodium or calcium channel blocker, a tricyclic antidepressant and acarbonic anhydrase inhibitor, a selective serotonin reuptake inhibitorand anti-seizure medication, a selective serotonin reuptake inhibitorand a beta blocker, a selective serotonin inhibitor and a sodium orcalcium channel blocker, an anti-seizure medication and a sodium orcalcium channel blocker, and a sodium or calcium channel blocker and acarbonic anhydrase inhibitor. In yet a further embodiment of any of theforegoing embodiments, the two or more medications of the combinedtherapy are selected from the group consisting of: nortriptyline,topiramate, amitriptyline, gabapentin, propranolol, verapamil,acetazolamide, and paroxetine. In yet a further embodiment of any of theforegoing embodiments, combinations of the two or more medications ofthe combined therapy are selected from the group consisting of:nortriptyline and topiramate, nortriptyline and gabapentin,amitriptyline and topiramate, amitriptyline and gabapentin,nortriptyline and propranolol, amitriptyline and propranolol,nortriptyline and verapamil, amitriptyline and verapamil, nortriptylineand acetazolamide, amitriptyline and acetazolamide, paroxetine andtopiramate, paroxetine and gabapentin, paroxetine and propranolol,paroxetine and verapamil, paroxetine and acetazolamide, verapamil andtopiramate, verapamil and gabapentin, and verapamil and acetazolamide.In yet a further embodiment of any of the foregoing embodiments, the twoor more medications of the combined therapy are concomitantlyadministered. In yet a further embodiment of any of the foregoingembodiments, the two or more medications of the combined therapy aresequentially administered. In yet a further embodiment of any of theforegoing embodiments,

the two or more medications of the combined therapy is administered atless than about 75% of the maximal dose for the two or more medications.

DESCRIPTION OF DRAWINGS

FIG. 1 provides a diagram of the anatomy of a human ear.

FIG. 2 provides an embodiment of a 12-month course (timeline table) toinvestigate the combined therapy disclosed herein in a large,randomized, double-blinded, and placebo-controlled study.

DETAILED DESCRIPTION

As used herein and in the appended claims, the singular forms “a,” “an,”and “the” include plural referents unless the context clearly dictatesotherwise. Thus, for example, reference to “a bleb” includes a pluralityof such vesicles and reference to “the extracellular vesicle” includesreference to one or more extracellular vesicles and equivalents thereofknown to those skilled in the art, and so forth.

Also, the use of “or” means “and/or” unless stated otherwise. Similarly,“comprise,” “comprises,” “comprising” “include,” “includes,” and“including” are interchangeable and not intended to be limiting.

It is to be further understood that where descriptions of variousembodiments use the term “comprising,” those skilled in the art wouldunderstand that in some specific instances, an embodiment can bealternatively described using language “consisting essentially of” or“consisting of.”

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood to one of ordinary skill inthe art to which this disclosure belongs. Although many methods andreagents are similar or equivalent to those described herein, theexemplary methods and materials are disclosed herein.

All publications mentioned herein are incorporated herein by referencein full for the purpose of describing and disclosing the methodologies,which might be used in connection with the description herein. Moreover,with respect to any term that is presented in one or more publicationsthat is similar to, or identical with, a term that has been expresslydefined in this disclosure, the definition of the term as expresslyprovided in this disclosure will control in all respects.

It should be understood that this invention is not limited to theparticular methodology, protocols, and reagents, etc., described hereinand as such may vary. The terminology used herein is for the purpose ofdescribing particular embodiments only and is not intended to limit thescope of the present invention, which is defined solely by the claims.

Other than in the operating examples, or where otherwise indicated, allnumbers expressing quantities of ingredients or reaction conditions usedherein should be understood as modified in all instances by the term“about.” The term “about” when used to described the present invention,in connection with percentages means±1%.

The term “co-administration”, “in combination with”, “a combination of”or “administered along with” may be used interchangeably and, as usedherein, refers to two or more medical agents (e.g., drugs) being foundin the patient's bloodstream at the same time, regardless of when or howthey are actually administered. In one embodiment, the agents areadministered simultaneously. In another embodiment, administration incombination is accomplished by combining the agents in a single dosageform. In yet another embodiment, the agents are administeredsequentially. In a further embodiment the agents are administeredthrough the same route. For example, in some embodiments, both agentsare administered orally. In yet a further embodiment, the agents areadministered through different routes. For example, in one embodiment,one agent is administered orally and the other agent is administeredparenterally.

The terms “patient”, “subject” and “individual” are used interchangeablyherein, and refer to an animal, particularly a human, to whom treatmentincluding prophylaxis treatment is provided. This includes human andnon-human animals. The term “non-human animals” and “non-human mammals”are used interchangeably herein includes all vertebrates, e.g., mammals,such as non-human primates, (particularly higher primates), sheep, dog,rodent (e.g., mouse or rat), guinea pig, goat, pig, cat, rabbits, cows,and non-mammals such as chickens, amphibians, reptiles etc. In oneembodiment, the subject is human. In another embodiment, the subject isan experimental animal or animal substitute as a disease model. “Mammal”refers to any animal classified as a mammal, including humans, non-humanprimates, domestic and farm animals, and zoo, sports, or pet animals,such as dogs, cats, cattle, horses, sheep, pigs, goats, rabbits, etc.Patient or subject includes any subset of the foregoing, e.g., all ofthe above, but excluding one or more groups or species such as humans,primates or rodents. A subject can be male or female. A subject can be afully developed subject (e.g., an adult) or a subject undergoing thedevelopmental process (e.g., a child, infant or fetus).

The term “pharmaceutically acceptable” refers to molecular entities andcompositions that are “generally regarded as safe”—e.g., that arephysiologically tolerable and do not typically produce an allergic orsimilar untoward reaction, such as gastric upset and the like, whenadministered to a human. In embodiments, this term refers to molecularentities and compositions approved by a regulatory agency of the federalor a state government, as the GRAS list under section 204(s) and 409 ofthe Federal Food, Drug and Cosmetic Act, that is subject to premarketreview and approval by the FDA or similar lists, the U.S. Pharmacopeiaor another generally recognized pharmacopeia for use in animals, andmore particularly in humans.

The term “therapeutically effective amount” as used herein, refers to anamount that is sufficient to affect a therapeutically significantreduction in one or more symptoms of the condition when administered toa typical subject who has the condition. A therapeutically significantreduction in a symptom is, e.g., about 10%, about 20%, about 30%, about40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%,or more as compared to a control or non-treated subject.

The term “treat” or “treatment” as used herein, refers to a therapeutictreatment wherein the object is to eliminate or lessen a condition or asymptom. Beneficial or desired clinical results include, but are notlimited to, elimination of symptoms or a condition, alleviation ofsymptoms or a condition, diminishment of extent of the condition orsymptom, stabilization (i.e., not worsening) of the state of thecondition or symptom, and delay or slowing of progression of thecondition or symptoms. In a particular embodiment, treatment of asubject with a combined medical therapy disclosed herein results inimprovement in a subject's tinnitus functional index; a decrease in theaverage number days in which the subject has annoying tinnitus; adecrease in the level of tinnitus loudness; and/or improvement in auralpressure/pain, fluctuating hearing loss, dizziness/vertigo, neckstiffness/headache, irritable bowel syndrome/interstitial cystitis,and/or fibromyalgia.

Tinnitus is defined as a perception of sound in the absence of externalstimuli. Tinnitus is characterized by an auditory sensation in theabsence of external sound. In many cases tinnitus is subjectivelyperceptual, i.e., only the subject can perceive symptoms. Symptoms oftinnitus include ringing, roaring, static, buzzing, hissing andwhistling in one or both ears. The noise may be intermittent orcontinuous. In a nationwide study in the United States, about 50 millionindividuals (aged 20 years or older) reported having tinnitus in thepreceding 12 months, with 16 million reporting tinnitus to occur atleast once a day. In a cross-sectional analysis of U.S. representativedemographic and audiometric data, it was shown that approximately 2.5million individuals aged 12 to 19 years in the United States haveexperienced at least one episode of tinnitus, and this condition ischronic in about 1.6 million individuals in the same age category. Ifleft untreated, tinnitus may lead to mental and psychological problems,such as depression, anxiety, panic, and cognitive defects, especially inolder patients. It also represents one of the most common anddistressing problems in otology practice, and it causes various somaticand psychological disorders that interfere with the quality of life.Despite many studies designed to find the mechanisms causing tinnitus,its pathophysiology remains poorly understood. In spite of the largeeconomic and emotional impact of tinnitus, currently there is noFDA-approved medication to treat this debilitating condition.

Current treatments for tinnitus can be categorized into dietary andlifestyle modifications, medical treatments, cognitive behavioraltherapy, and sound therapy. However, there is no FDA-approved medicinefor treatment of tinnitus. The medications most often used in tinnitusmanagement are psychoactive drugs that treat psychological issuesarising from tinnitus. These drugs can help relieve the stress, anxiety,and depression related to tinnitus, minimizing the psychological burdenof the condition. Because there is a circular relationship betweennegative emotions and tinnitus (tinnitus causes anxiety, which makestinnitus seem worse, which causes more anxiety, etc.), it is alsopossible that psychoactive drugs may make tinnitus itself lessnoticeable for some patients. The Cochrane Library reveals six clinicaltrials (including 610 patients) evaluated the effectiveness ofantidepressants in treatment of tinnitus. However, the trials' qualitywas generally low and none of them met the highest quality standard dueto use of inadequate outcome measures and large drop-out rates. Hence,they concluded there is as yet insufficient evidence to say thatantidepressant drug therapy improves tinnitus and further research isrequired.

The last decade saw an uptick in reports possibly implicating that thereis a relationship between tinnitus and migraine. Such findings, however,were in direct contrast with the previously held and popular notion thatmigraine will seldom have a negative impact on the auditory pathways andgenerate cochlear symptoms, such as hearing loss or tinnitus. Recentstudies showed that between 26-47% of patients with tinnitus suffer fromconcomitant headache, which was further supported by a large-scalecohort study.

A growing number of neuroimaging studies have been published in recentyears consistently describing pathophysiological changes in brainregions beyond the auditory system, specifically in limbic structures.When analyzing these structural and functional changes associated withtinnitus, one can appreciate the anatomical overlap with thefronto-subcortical loop circuits affected in mood and anxiety disorders.The mechanism by which these changes are facilitated in tinnitus remainsunknown, although various hypotheses have been proposed in the art.Although the pathophysiology of tinnitus and mood, anxiety or paindisorders will certainly be different, the functional neuroanatomy andsome basic physiological principles (i.e., maladaptive plasticity) maynot be that different. The study showed that the cumulative incidence ofcochlear symptoms, defined as tinnitus, hearing loss, and/or suddendeafness was significantly higher in patients with history of migraineheadaches than those without a migraine history.

It is postulated herein that migraine-related cochlear (i.e., tinnitus,hearing loss) and vestibular (balance) symptoms can result fromcompromised blood flow to the inner ear (see FIG. 1) and to the brain asa result of vasospasm of the branches of the posterior cerebralcirculation as well as possibly trigeminal neurogenic inflammation. Itwas postulated herein, that even patients without depression or otherneuropsychiatric symptoms would benefit from receiving antidepressantdrugs, such as nortriptyline and amitriptyline, due to a similar orcommon pathophysiological basis. In other words, one of the possibleexplanations for association of pain (i.e., headache) and tinnitus isthalamocortical dysrhythmia. In this proposed model, development of yband activity related to the tinnitus percept serves as thepathophysiological model linking these two conditions. Tinnitus(similarly to chronic pain) may further have a peripheral physiologicalorigin, but then the stimulus becomes established in the brain. Forexample, a correlation between the subjective strength of stimulus andthe amount of cortical reorganization, is in line with studies lookingat phantom limb pain in upper extremity amputees.

Based upon the foregoing analysis, an innovative approach was developedherein for the treatment of tinnitus that utilizes novel combinations ofmedications as well as other treatment options. In a further embodiment,the disclosure further provides for a step-wise combined treatmentregimen comprising of an algorithm of escalating doses of a firstmedication (e.g., nortriptyline (antidepressant)) to a second medication(e.g., topiramate (anti-seizure medication)). The escalation of thedoses can be based on patient symptoms and the severity thereof. Forexample, if the first medication is nortriptyline, nortriptyline can betitrated from 7.5 mg up to 60 mg in 7.5 mg steps. Similarly, if thesecond mediation is topiramate, topiramate can be titrated from 10 mg upto 80 mg in 10 mg steps every week concurrently with step-wiseadjustment of the first medication, like nortriptyline. Given the riskof intolerance or possible side effects with migraine medications,patients are often started on a low dose with gradual escalation iftheir symptoms are not controlled. Based upon empiric and clinicalexperiences, it is believed that the combined therapy disclosed hereinis efficacious with a small negative side-effect profile. For instance,in previous studies on Meniere's disease (in which tinnitus is one ofthe main symptoms), it was found that tinnitus-related quality of lifescores increased (improved quality of life) from 0.91±1.08 pre-treatmentto 1.26±1.32 post-treatment (p<0.001) with a combined therapy treatment.

In view positive results of pilot studies demonstrating efficacy of thecombined treatment regimens disclosed herein, a randomizeddouble-blinded placebo-controlled large-scale studies are currentlybeing considered for tinnitus and other conditions, including dizziness,fluctuating or sudden hearing loss, sensorineural hearing loss, anddizziness. Further, it is expected that the large studies would utilizea step-wise regimen as described above. The subjects will be randomlyassigned to experimental and control groups. The experimental group willreceive combined treatment regimen (e.g., use of nortriptyline withtopiramate) and the control group will receive a placebo daily. Bothgroups will be followed up over a course of 8 weeks. Primary treatmentoutcomes will be evaluated, and potential adverse events will berecorded for safety analysis. Secondary treatment outcomes will also beevaluated. Preliminary clinical data in a retrospective analysis ofpatients treated with the proposed medications have shown improvement inprimary and secondary treatment outcomes, suggesting potentialeffectiveness of these treatments.

Further follow-on studies will look at the most effective dosage of thecombined therapy. In such studies, subjects in the experimental groupwill start the study using an initial low dosage of the first and secondmedications. Such a dosage may be administered concurrently (e.g., useof single dosage form that comprises both medications) or sequentially(e.g., use of separate dosage forms administered at different timepoints). On a weekly basis, the subjects will be instructed to increasethe dosage of the first and second medications if their symptoms do notimprove. This process will continue until a maximum safe dosage isreached. Subjects will further be instructed to avoid increasing theirmedication dosage if their symptoms are under control. Subjects in thecontrol group will also be asked to increase the dosage of placebodosage form(s) (provided to be similar to the dosage forms used in theexperimental group) every week if they do not experience improvement insymptoms. Those reporting side effects will be seen and examined toassess the safety of their continued enrollment and/or need foradditional treatment.

The disclosure provides for a combined therapy that was shown to haveefficacy based upon preliminary clinical data in a retrospectiveanalysis of patients treated with the medications which showedimprovement in primary and secondary treatment outcomes. Morespecifically it was found that a combination of medications fromdifferent drug classes provides beneficial or ameliorative effects intreating otologic conditions (e.g., tinnitus or vertigo) or an otologicsymptom (e.g., tinnitus or vertigo) associated with a disease ordisorder (e.g., headache or inflammatory intestinal disorder) in asubject in need thereof. For example, retrospective analysis of thepreliminary clinical data indicated that an otologic condition orotologic symptom associated with a disease or disorder disclosed hereincan be treated with a combined therapy of two or more drugs selectedfrom the following drug classes: tricyclic antidepressants, anti-seizuremedications, beta blockers, carbonic anhydrase inhibitors, selectiveserotonin reuptake inhibitors, selective norepinephrine reuptakeinhibitors, calcium or sodium channel blockers, serotonin norepinephrinereuptake inhibitors, specific serotonin antidepressants, tetracyclic andunicyclic antidepressants, tricyclic secondary amines, tricyclictertiary amines, and antidepressants/serotonin modulators. Examples oftricyclic antidepressants include, but are not limited to, amineptine,amitriptyline, amitriptylinoxide butriptyline, clomipramine,demexiptiline, desipramine, dibenzepin, dimetacrine, dosulepin, doxepin,imipramine, imipraminoxide, iprindole, lofepramine, melitracen,metapramine, nitroxazepine, nortriptyline, noxiptiline, opipramol,pipofezine, propizepine, protriptyline, quinupramine, tianeptine, andtrimipramine. Examples of anti-seizure medications include, but are notlimited to, acetazolamide, carbamazepine, clobazam, clonazepam,diazepam, divalproex sodium, ethosuximide, ethotoin, felbamate,fosphenytoin, gabapentin, lamotrigine, lacosamide, levetiracetam,lorazepam, mephenytoin, metharbital, methsuximide, methazolamide,nitrazepam, oxcarbazepine, phenobarbital, phenytoin, phensuximide,pregabalin, primidone, rufinamide, sodium valproate, stiripentol,tiagabine, topiramate, trimethadione, valproic acid, vigabatrin, andzonisamide. Examples of beta blockers include, but are not limited to,alprenolol, bopindolol, bupranolol, carteolol, cloranolol, mepindolol,nadolol, oxprenolol, penbutolol, pindolol, iodopindolol, propranolol,sotalol, tertatolol, timolol, acebutolol, atenolol, betaxolol,bevantolol, bisoprolol, celiprolol, epanolol, esmolol, landiolol,metoprolol, nebivolol, practolol, S-atenolol, talinolol, butaxamine,arotinolol, carvedilol, and labetalol. Examples of carbonic anhydraseinhibitors include, but are not limited to, acetazolamide,dichlorphenamide, and zonisamide. Examples of selective serotoninreuptake inhibitors, include but are not limited to, citalopram,escitalopram, fluoxetine, fluvoxamine, indalpine, paroxetine,sertraline, and zimelidine. Examples of selective norepinephrinereuptake inhibitors, include but are not limited to, desvenlafaxine,duloxetine, levomilnacipran, milnacipran, tofenacin, and venlafaxine.Examples of calcium or sodium channel blockers, include but are notlimited to, ethadione, paramethadione, trimethadione, ethosuximide,mesuximide, phensuximide, gabapentin, pregabalin, imepitoin,lamotrigine, topiramate, verapamil and zonisamide. Examples oftetracyclic and unicyclic antidepressants include, but are not limitedto, bupropion, amoxapine, mirtazapine, and maprotiline.

In a further embodiment, the combined therapy disclosed herein to treatan otologic condition or symptom (e.g., tinnitus and vertigo) associatedwith a disease or disorder (e.g., headache or inflammatory intestinaldisorder) comprises a tricyclic antidepressant used in combination withan anti-seizure medication, a calcium or sodium channel blocker, a betablocker, a carbonic anhydrase inhibitor, a selective serotonin reuptakeinhibitor, and/or a selective norepinephrine inhibitor. In yet a furtherembodiment, the combined therapy disclosed herein to treat and otologiccondition or symptom (e.g., tinnitus and vertigo) associated with adisease or disorder (e.g., headache or inflammatory intestinal disorder)comprises an anti-seizure medication used in combination with a calciumor sodium channel blocker, beta blocker, and/or carbonic anhydraseinhibitor. In another embodiment, the combined therapy disclosed hereinto treat and otologic condition or symptom (e.g., tinnitus and vertigo)associated with a disease or disorder (e.g., headache or inflammatoryintestinal disorder) comprises a selective serotonin reuptake inhibitorused in combination with an anti-seizure medication, calcium or sodiumchannel blocker, beta blocker, and/or carbonic anhydrase inhibitor. Inyet another embodiment, the combined therapy disclosed herein to treatand otologic condition or symptom (e.g., tinnitus and vertigo)associated with a disease or disorder (e.g., headache or inflammatoryintestinal disorder) comprises a calcium or sodium channel blocker usedin combination with a carbonic anhydrase inhibitor.

The disclosure provides compositions for treating an otologic condition(e.g., tinnitus) or an otologic symptom (e.g., tinnitus and vertigo)associated with a disease or disorder (e.g., headache or inflammatoryintestinal disorder). The compositions of the disclosure comprise afirst medication and a second medication selected from the followingdrug classes: tricyclic antidepressants, anti-seizure medications, betablockers, carbonic anhydrase inhibitors, selective serotonin reuptakeinhibitors, selective norepinephrine reuptake inhibitors, calcium orsodium channel blockers, serotonin norepinephrine reuptake inhibitors,specific serotonin antidepressants, unicyclic antidepressants, tricyclicsecondary amines, tricyclic tertiary amines, andantidepressants/serotonin modulators, wherein the first medication andthe second medication are not from the same drug class. In a furtherembodiment, the composition of the disclosure comprises a firstmedication and a second medication in a ratio of 20:1 to 1:20, 19:1 to1:19, 18:1 to 1:18, 17:1 to 1:17, 16:1 to 1:16, 15:1 to 1:15, 14:1 to1:14, 13:1 to 1:13, 12:1 to 1:12, 11:1 to 1:11, 10:1 to 1:10, 9:1 to1:9, 8:1 to 1:8, 7:1 to 1:7, 6:1 to 1:6, 5:1 to 1:5, 4:1 to 1:4, 3:1 to1:3, 2:1 to 1:2, or 1:1.

The disclosure provides a composition which comprises a first medicationof nortriptyline and a second medication selected from an anti-seizuremedication, a beta blocker, a calcium or sodium channel blocker, and acarbonic anhydrase inhibitor. In another embodiment, a compositiondisclosed herein comprises nortriptyline at a dose of about 1 mg, 5 mg,10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110mg, 115 mg, 120 mg, 125 mg, or a range that includes or is between anytwo of the foregoing doses (e.g., from 1 mg to 125 mg of nortriptyline).In another embodiment, a composition of the disclosure comprises a firstmedication of nortriptyline and a second medication of topiramate. Inyet another embodiment, a composition of the disclosure comprises afirst medication of nortriptyline and a second medication of gabapentin.In a further embodiment, a composition of the disclosure comprises afirst medication of nortriptyline and a second medication of topiramate.In yet a further embodiment, a composition of the disclosure comprises afirst medication of nortriptyline and a second medication ofpropranolol. In another embodiment, a composition of the disclosurecomprises a first medication of nortriptyline and a second medication ofverapamil. In yet another embodiment, a composition of the disclosurecomprises a first medication of nortriptyline and a second medication ofacetazolamide.

The disclosure also provides a composition that comprises a firstmedication of amitriptyline and a second medication selected from ananti-seizure medication, a beta blocker, a calcium or sodium channelblocker, and a carbonic anhydrase inhibitor. In a further embodiment, acomposition disclosed herein comprises amitriptyline at a dose of about1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, or a range that includes oris between any two of the foregoing doses (e.g., from 1 mg to 125 mg ofamitriptyline). In a particular embodiment, a composition of thedisclosure comprises a first medication of amitriptyline and a secondmedication of topiramate. In another embodiment, a composition of thedisclosure comprises a first medication of amitriptyline and a secondmedication of gabapentin. In yet another embodiment, a composition ofthe disclosure comprises a first medication of amitriptyline and asecond medication of propranolol. In a further embodiment, a compositionof the disclosure comprises a first medication of amitriptyline and asecond medication of verapamil. In yet a further embodiment, acomposition of the disclosure comprises a first medication ofamitriptyline and a second medication of acetazolamide.

The disclosure further provides a composition that comprises a firstmedication of propranolol and a second medication selected from atricyclic antidepressant and a selective serotonin reuptake inhibitor.In yet another embodiment, a composition disclosed herein comprisespropranolol at a dose of about 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg,35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg or a range thatincludes or is between any two of the foregoing doses (e.g., from 9 mgto 160 mg of propranolol). In a further embodiment, a composition of thedisclosure comprises a first medication of propranolol and a secondmedication of nortriptyline. In yet a further embodiment, a compositionof the disclosure comprises a first medication of propranolol and asecond medication of amitriptyline. In another embodiment, a compositionof the disclosure comprises a first medication of propranolol and asecond medication of paroxetine.

In yet another embodiment, the disclosure provides for a compositionthat comprises a first medication of topiramate and a second medicationselected from a tricyclic antidepressant, a selective serotonin reuptakeinhibitor, a calcium or sodium channel blocker. In a certain embodiment,a composition disclosed herein comprises topiramate at a dose of about 7mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195mg, 200 mg, or a range that includes or is between any two of theforegoing doses (e.g., from 7 mg to 200 mg of topiramate). In a furtherembodiment, a composition of the disclosure comprises a first medicationof topiramate and a second medication of nortriptyline. In anotherembodiment, a composition of the disclosure comprises a first medicationof topiramate and a second medication of amitriptyline. In yet anotherembodiment, a composition of the disclosure comprises a first medicationof topiramate and a second medication of paroxetine. In anotherembodiment, a composition of the disclosure comprises a first medicationof topiramate and a second medication of verapamil.

The disclosure also provides a composition that comprises a firstmedication of gabapentin and a second medication selected from atricyclic antidepressant, a selective serotonin reuptake inhibitor, acalcium or sodium channel blocker. In a certain embodiment, acomposition disclosed herein comprises gabapentin at a dose of about 40mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550mg, 2600 mg, 2650 mg, 2700 mg, or a range that includes or is betweenany two of the foregoing doses (e.g., from 40 mg to 2700 mg ofgabapentin). In a further embodiment, a composition of the disclosurecomprises a first medication of gabapentin and a second medication ofnortriptyline. In another embodiment, a composition of the disclosurecomprises a first medication of gabapentin and a second medication ofamitriptyline. In yet another embodiment, a composition of thedisclosure comprises a first medication of gabapentin and a secondmedication of paroxetine. In another embodiment, a composition of thedisclosure comprises a first medication of gabapentin and a secondmedication of verapamil.

The disclosure provides a composition that comprises a first medicationof verapamil and a second medication selected from a tricyclicantidepressant, a selective serotonin reuptake inhibitor, a calcium orsodium channel blocker, and a carbonic anhydrase inhibitor. In a certainembodiment, a composition disclosed herein comprises verapamil at a doseof about 20 mg, 40 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg,350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg,800 mg, 850 mg, 900 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg,1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg,1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg,2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg,2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, or a range thatincludes or is between any two of the foregoing doses (e.g., from 20 mgto 2700 mg of verapamil). In a further embodiment, a composition of thedisclosure comprises a first medication of verapamil and a secondmedication of nortriptyline. In another embodiment, a composition of thedisclosure comprises a first medication of verapamil and a secondmedication of amitriptyline. In yet another embodiment, a composition ofthe disclosure comprises a first medication of verapamil and a secondmedication of paroxetine. In a further embodiment, a composition of thedisclosure comprises a first medication of verapamil and a secondmedication of topiramate. In another embodiment, a composition of thedisclosure comprises a first medication of verapamil and a secondmedication of gabapentin. In yet another embodiment, a composition ofthe disclosure comprises a first medication of verapamil and a secondmedication of acetazolamide.

The disclosure provides a composition that comprises a first medicationof acetazolamide and a second medication selected from a tricyclicantidepressant, and a calcium or sodium channel blocker. In a certainembodiment, a composition disclosed herein comprises acetazolamide at adose of about 60 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850mg, 900 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, or a range that includes or isbetween any two of the foregoing doses (e.g., from 60 mg to 1500 mg ofacetazolamide). In another embodiment, a composition of the disclosurecomprises a first medication of acetazolamide and a second medication ofnortriptyline. In yet another embodiment, a composition of thedisclosure comprises a first medication of acetazolamide and a secondmedication of amitriptyline. In a certain embodiment, a composition ofthe disclosure comprises a first medication of acetazolamide and asecond medication of paroxetine.

The disclosure provides a composition that comprises a first medicationof paroxetine and a second medication selected from an antiseizuremedication, a calcium or sodium channel blocker, a beta blocker, and acarbonic anhydrase inhibitor. In a certain embodiment, a compositiondisclosed herein comprises paroxetine at a dose of about 3 mg, 5 mg, 10mg, 12 mg, 14 mg, 15 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 25 mg, 26mg, 28 mg, 30 mg, 32 mg, 34 mg, 35 mg, 36 mg, 38 mg, 40 mg, or a rangethat includes or is between any two of the foregoing doses (e.g., from 3mg to 40 mg of paroxetine). In another embodiment, a composition of thedisclosure comprises a first medication of paroxetine and a secondmedication of topiramate. In yet another embodiment, a composition ofthe disclosure comprises a first medication of paroxetine and a secondmedication of gabapentin. In a certain embodiment, a composition of thedisclosure comprises a first medication of paroxetine and a secondmedication of verapamil. In a certain embodiment, a composition of thedisclosure comprises a first medication of paroxetine and a secondmedication of acetazolamide.

It is further expected that a composition of the disclosure could befurther combined with a dietary supplement in treating said ontologicalconditions or otologic symptom associated with a disease or disorder ina subject in need thereof. Examples of dietary supplements, include butare not limited to, vitamin supplements (e.g., vitamin B₂), mineralsupplements (e.g., magnesium), specialty supplements (e.g., melatonin,glucosamine, fish oil, etc.) or a botanical or herbal supplement (e.g.,feverfew).

The disclosure further provides that a composition disclosed herein isformulated as a pharmaceutical composition in a single unit dosage form,or a multi-unit dosage form. Such pharmaceutical compositions maycomprise physiologically acceptable surface-active agents, carriers,diluents, excipients, smoothing agents, suspension agents, film formingsubstances, and coating assistants, or combinations thereof. Acceptablecarriers or diluents for therapeutic use are well known in thepharmaceutical art, and are described, for example, in Remington'sPharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa.(1990), which is incorporated herein by reference in its entirety.Preservatives, stabilizers, dyes, sweeteners, fragrances, flavoringagents, and the like may be provided in the pharmaceutical composition.For example, sodium benzoate, ascorbic acid and esters ofp-hydroxybenzoic acid may be added as preservatives. In addition,antioxidants and suspending agents may be used. In various embodiments,alcohols, esters, sulfated aliphatic alcohols, and the like may be usedas surface active agents; sucrose, glucose, lactose, starch,crystallized cellulose, mannitol, light anhydrous silicate, magnesiumaluminate, magnesium metasilicate aluminate, synthetic aluminumsilicate, calcium carbonate, sodium acid carbonate, calcium hydrogenphosphate, calcium carboxymethyl cellulose, and the like may be used asexcipients; magnesium stearate, talc, hardened oil and the like may beused as smoothing agents; coconut oil, olive oil, sesame oil, peanutoil, soya may be used as suspension agents or lubricants; celluloseacetate phthalate as a derivative of a carbohydrate such as cellulose orsugar, or methyl acetate-methacrylate copolymer as a derivative ofpolyvinyl may be used as suspension agents; and plasticizers such asester phthalates and the like may be used as suspension agents.

The term “carrier” defines a chemical compound that facilitates theincorporation of medications disclosed herein into cells or tissues. Forexample, dimethyl sulfoxide (DMSO) is a commonly utilized carrier as itfacilitates the uptake of many organic compounds into the cells ortissues of an organism.

The term “diluent” defines a chemical compound that will dissolve themedications of interest as well as stabilize the biologically activeform of the medication. Salts dissolved in buffered solutions areutilized as diluents in the art. One commonly used buffered solution isphosphate buffered saline because it mimics the salt conditions of humanblood. Since buffer salts can control the pH of a solution at lowconcentrations, a buffered diluent rarely modifies the biologicalactivity of a medication.

The term “physiologically acceptable” defines a carrier or diluent thatdoes not abrogate the biological activity and properties of themedications disclosed herein.

Techniques for formulation and administration of the compositionsdescribed herein may be found in “Remington's Pharmaceutical Sciences,”Mack Publishing Co., Easton, Pa., 18th edition, 1990.

Suitable routes of administration of the pharmaceutical composition may,for example, include oral, rectal, transmucosal, topical, or intestinaladministration; parenteral delivery, including intramuscular,subcutaneous, intravenous, intramedullary injections, as well asintrathecal, direct intraventricular, intraperitoneal, intranasal, orintraocular injections. The pharmaceutical composition can also beadministered in sustained or controlled release dosage forms, includingdepot injections, osmotic pumps, pills, transdermal (includingelectrotransport) patches, and the like, for prolonged and/or timed,pulsed administration at a predetermined rate.

The pharmaceutical compositions of the present invention may bemanufactured in a manner that is itself known, e.g., by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or tableting processes.

Pharmaceutical compositions for use as described herein thus may beformulated in conventional manner using one or more physiologicallyacceptable carriers comprising excipients and auxiliaries whichfacilitate processing of the active medications into preparations whichcan be used pharmaceutically. Proper formulation is dependent upon theroute of administration chosen. Any of the well-known techniques,carriers, and excipients may be used as suitable and as understood inthe art; e.g., in Remington's Pharmaceutical Sciences, above.

Injectables can be prepared in conventional forms, either as liquidsolutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. Suitableexcipients are, for example, water, saline, dextrose, mannitol, lactose,lecithin, albumin, sodium glutamate, cysteine hydrochloride, and thelike. In addition, if desired, the injectable pharmaceuticalcompositions may contain minor amounts of nontoxic auxiliary substances,such as wetting agents, pH buffering agents, and the like.Physiologically compatible buffers include, but are not limited to,Hanks's solution, Ringer's solution, or physiological saline buffer. Ifdesired, absorption enhancing preparations (for example, liposomes), maybe utilized.

For transmucosal administration, penetrants appropriate to the barrierto be permeated may be used in the formulation.

Pharmaceutical formulations for parenteral administration, e.g., bybolus injection or continuous infusion, include aqueous solutions of theactive medications in water-soluble form. Additionally, suspensions ofthe active compounds may be prepared as appropriate oily injectionsuspensions. Suitable lipophilic solvents or vehicles include fatty oilssuch as sesame oil, or other organic oils such as soybean, grapefruit oralmond oils, or synthetic fatty acid esters, such as ethyl oleate ortriglycerides, or liposomes. Aqueous injection suspensions may containsubstances which increase the viscosity of the suspension, such assodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, thesuspension may also contain suitable stabilizers or agents that increasethe solubility of the compounds to allow for the preparation of highlyconcentrated solutions. Formulations for injection may be presented inunit dosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Alternatively, the medications may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

For oral administration, the medications can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained by combining the active compounds with solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired,disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate. Dragee cores are provided with suitable coatings. For thispurpose, concentrated sugar solutions may be used, which may optionallycontain gum arabic, talc, polyvinyl pyrrolidone, Carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures. Dyestuffs or pigments maybe added to the tablets or dragee coatings for identification or tocharacterize different combinations of active compound doses. For thispurpose, concentrated sugar solutions may be used, which may optionallycontain gum arabic, talc, polyvinyl pyrrolidone, Carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures. Dyestuffs or pigments maybe added to the tablets or dragee coatings for identification or tocharacterize different combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the medications may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal administration, the pharmaceutical compositions may take theform of tablets or lozenges formulated in conventional manner.

For administration by inhalation, the compositions for use according tothe present invention are conveniently delivered in the form of anaerosol spray presentation from pressurized packs or a nebulizer, withthe use of a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, e.g., gelatin for use in an inhaler orinsulator may be formulated containing a powder mix of the medicationsand a suitable powder base such as lactose or starch.

Further disclosed herein are various pharmaceutical compositions wellknown in the pharmaceutical art for uses that include intraocular,intranasal, and intra-auricular delivery. Suitable penetrants for theseuses are generally known in the art. Pharmaceutical compositions forintraocular delivery include aqueous ophthalmic solutions of the activecompounds in water-soluble form, such as eyedrops, or in gellan gum(Shedden et al., Clin. Ther., 23(3):440-50 (2001)) or hydrogels (Mayeret al., Opthalmologica, 210(2):101-3 (1996)); ophthalmic ointments;ophthalmic suspensions, such as microparticulates, drug-containing smallpolymeric particles that are suspended in a liquid carrier medium(Joshi, A., J. Ocil. Pharmacol., 10(1):29-45 (1994)), lipid-solubleformulations (Alm et al., Prog. Clin. Biol. Res., 312:447-58 (1989)),and microspheres (Mordenti, Toxicol. Sci., 52(1):101-6 (1999)); andocular inserts. All of the above-mentioned references, are incorporatedherein by reference in their entireties. Such suitable pharmaceuticalformulations are most often and preferably formulated to be sterile,isotonic and buffered for stability and comfort. Pharmaceuticalcompositions for intranasal delivery may also include drops and spraysoften prepared to simulate in many respects nasal secretions to ensuremaintenance of normal ciliary action. As disclosed in Remington'sPharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa.(1990), which is incorporated herein by reference in its entirety, andwell-known to those skilled in the art, suitable formulations are mostoften and preferably isotonic, slightly buffered to maintain a pH of 5.5to 6.5, and most often and preferably include antimicrobialpreservatives and appropriate drug stabilizers. Pharmaceuticalformulations for intra-auricular delivery include suspensions andointments for topical application in the ear. Common solvents for suchaural formulations include glycerin and water.

The pharmaceutical composition may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

In addition to the pharmaceutical formulations described previously, themedications may also be formulated as a depot preparation. Such longacting formulations may be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds may be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

For hydrophobic compounds, a suitable pharmaceutical carrier may be acosolvent system comprising benzyl alcohol, a nonpolar surfactant, awater-miscible organic polymer, and an aqueous phase. A common cosolventsystem used is the VPD co-solvent system, which is a solution of 3% w/vbenzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™, and65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.Naturally, the proportions of a co-solvent system may be variedconsiderably without destroying its solubility and toxicitycharacteristics. Furthermore, the identity of the co-solvent componentsmay be varied: for example, other low-toxicity nonpolar surfactants maybe used instead of POLYSORBATE 80™; the fraction size of polyethyleneglycol may be varied; other biocompatible polymers may replacepolyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars orpolysaccharides may substitute for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are well knownexamples of delivery vehicles or carriers for hydrophobic drugs. Certainorganic solvents such as dimethyl sulfoxide also may be employed,although usually at the cost of greater toxicity. Additionally, thecompounds may be delivered using a sustained-release system, such assemipermeable matrices of solid hydrophobic polymers containing thetherapeutic agent. Various sustained-release materials have beenestablished and are well known by those skilled in the art.Sustained-release capsules may, depending on their chemical nature,release the compounds for a few weeks up to over 100 days. Depending onthe chemical nature and the biological stability of the therapeuticreagent, additional strategies for protein stabilization may beemployed.

Agents intended to be administered intracellularly may be administeredusing techniques well known to those of ordinary skill in the art. Forexample, such agents may be encapsulated into liposomes. All moleculespresent in an aqueous solution at the time of liposome formation areincorporated into the aqueous interior. The liposomal contents are bothprotected from the external micro-environment and, because liposomesfuse with cell membranes, are efficiently delivered into the cellcytoplasm. The liposome may be coated with a tissue-specific antibody.The liposomes will be targeted to and taken up selectively by thedesired organ. Alternatively, small hydrophobic organic molecules may bedirectly administered intracellularly.

The disclosure provides for methods of treatment of an otologiccondition or an otologic symptom associated with a disease or disorderin a subject in need thereof, comprising: administering atherapeutically effective amount of a composition or combined therapydisclosed herein. Examples of an otologic conditions and otologicsymptom include, but are not limited to, tinnitus, fluctuating or suddenhearing loss, sensorineural hearing loss, dizziness, and vertigo.Examples of disease or disorders that give rise to otologic symptoms,include but are not limited to, neck pain, headache, irritable bowelsyndrome, interstitial cystitis, migraine-related disorders, andfibromyalgia. In a certain embodiment, the disclosure provides for useof a composition or combined therapy disclosed herein for the treatmentof tinnitus in a subject in need thereof. In another embodiment, thedisclosure provides for use of a composition or combined therapydisclosed herein for the treatment of vertigo in a subject in needthereof. In yet another embodiment, the disclosure provides for use of acomposition or combined therapy disclosed herein for the treatment offluctuating or sudden hearing loss in a subject in need thereof. Inanother embodiment, the disclosure provides for use of a composition orcombined therapy disclosed herein for the treatment of dizziness in asubject in need thereof. In yet another embodiment, the disclosureprovides for use of a composition or combined therapy disclosed hereinfor the treatment of sensorineural hearing loss in a subject in needthereof.

In some embodiments, one of the advantages of the compositions andcombined therapies disclosed herein is that medications can beco-administered at a sub-maximal dose levels and still achieve anefficacious result. In doing so, use of the compositions composition andcombined therapies described herein can avoid side-effects seen when themedications are administered alone at a maximal dose. In variousembodiments, the side effects are selected from the group consisting ofstroke, tremors, sedation, gastrointestinal problems, neurologicalproblems, increased risk of death, cerebrovascular events, movementdisorder, dystonia, akathisia, Parkinson's movement disorder, tardivedyskinesia, cognitive disorders, prolactinoma, catalepsy, psychosis,neuroleptic malignant syndrome, heart problems, pulmonary problems,diabetes, liver failure, suicidality, sedation, orthostatic hypotension,choking, dizziness, tachycardia, blood abnormalities (including abnormaltriglyceride levels, increased cholesterol levels, dyslipidemia, andhyperglycemia), syncope, seizures, dysphagia, priapism, thromboticthrombocytopenic purpura, disruption of body temperature regulation,insomnia, agitation, anxiety, somnolence, aggressive reaction, headache,constipation, nausea, dyspepsia, vomiting, abdominal pain, salivaincrease, toothache, rhinitis, coughing, sinusitis, pharyngitis,dyspnea, back pain, chest pain, fever, rash, dry skin, seborrhea,increased upper respiratory infection, abnormal vision, arthralgia,hypoesthesia, manic reaction, concentration impairment, dry mouth, pain,fatigue, acne, pruritus, myalgia, skeletal pain, hypertension, diarrhea,confusion, asthenia, urinary incontinence, sleepiness, increasedduration of sleep, accommodation disturbance, palpitations, erectiledysfunction, ejaculatory dysfunction, orgasmic dysfunction, lassitude,increased pigmentation, increased appetite, automatism, increased dreamactivity, diminished sexual desire, nervousness, depression, apathy,catatonic reaction, euphoria, increased libido, amnesia, emotionalliability, nightmares, delirium, yawning, dysarthria, vertigo, stupor,paranesthesia, aphasia, hypoesthesia, tongue paralysis, leg cramps,torticollis, hypotonia, coma, migraine, hyperreflexia, choreoathetosis,anorexia, flatulence, stomatitis, melena, hemorrhoids, gastritis, fecalincontinence, eructation, gastroesophageal reflux, gastroenteritis,esophagitis, tongue discoloration, cholelithiasis, tongue edema,diverticulitis, gingivitis, discolored feces, gastrointestinalhemorrhage, hematemesis, edema, rigors, malaise, pallor, enlargedabdomen, ascites, sarcoidosis, flushing, hyperventilation, bronchospasm,pneumonia, stridor, asthma, increased sputum, aspiration,photosensitivity, increased sweating, acne, decreased sweating,alopecia, hyperkeratosis, skin exfoliation, bullous eruption, skinulceration, aggravated psoriasis, furunculosis, verruca, dermatitislichenoid, hypertrichosis, genital pruritus, urticaria, ventriculartachycardia, angina pectoris, premature atrial contractions, T waveinversion, ventricular extrasystoles, ST depression, AV block,myocarditis, abnormal accommodation, xerophthalmia, diplopia, eye pain,blepharitis, photopsia, photophobia, abnormal lacrimation, hyponatremia,creatine phosphokinase increase, thirst, weight decrease, decreasedserum iron, cachexia, dehydration, hypokalemia, hypoproteinemia,hyperphosphatemia, hypertriglyceridemia, hyperuricemia, hypoglycemia,polyuria, polydipsia, hematuria, dysuria, urinary retention, cystitis,renal insufficiency, arthrosis, synostosis, bursitis, arthritis,menorrhagia, dry vagina, nonpuerperal lactation, amenorrhea, femalebreast pain, leukorrhea, mastitis, dysmenorrhea, female perineal pain,intermenstrual bleeding, vaginal hemorrhage, increased SGOT, increasedSGPT, cholestatic hepatitis, cholecystitis, hepatitis, hepatocellulardamage, epistaxis, superficial phlebitis, thrombophlebitis,thrombocytopenia, tinnitus, hyperacusis, decreased hearing, anemia,hypochromic anemia, normocytic anemia, granulocytopenia, leukocytosis,lymphadenopathy, leucopenia, Pelger-Huet anomaly, gynecomastia, malebreast pain, antidiuretic hormone disorder, bitter taste, micturitiondisturbances, oculogyric crisis, abnormal gait, involuntary musclecontraction, and increased injury.

In some embodiments, one or more of the medications of a composition orcombined therapy disclosed herein is administered at a sub-maximaldosage level. In various such embodiments, the dosage of one or more ofthe medications of the composition or combination therapy disclosedherein is less than about 75%, 60%, 50%, 40%, 30%, 20%, or 10% of themaximal dose. By “maximal dose,” it is meant the minimum dose wherefurther increases in the dose do not result in any significant increasein therapeutic effect when administering the agent alone. In someembodiments, one or more of the medications of the composition orcombination therapy disclosed herein is administered at a dose that isless than an efficacious dose for the medications when they areadministered alone. In various embodiments, the dosage is less thanabout 75%, 60%, 50%, 40%, 30%, 20%, or 10% of an efficacious dose. By“efficacious dose,” it is meant the minimal dosage that is required toachieve a clinically relevant therapeutic effect when administering theagent alone.

In some embodiments, administration of a composition or combined therapydisclosed herein results in a rapid onset of an efficacious effect. Inother words, in some embodiments, efficacious activity is achievedfaster than when the medications are used in combination than when theyare singly administered. In various embodiments, the rapid onset ofefficacious activity is demonstrated by a clinically relevanttherapeutic effect being achieved greater than about 30%, 40%, 50%, 60%,70%, 80%, 90%, 100%, 110%, 130%, 150%, 200%, 300%, 400%, or 500% fasterthan when the medications are administered alone at an efficacious dose.In some embodiments, the rapid onset of efficacious activity isdemonstrated by a greater percentage of patients experiencing anefficacious effect after a specified period of time of the combinedtherapy when compared to administration of the medications singly at anefficacious dose. In various embodiments, the percentage of patientsexperiencing an efficacious effect from the combined therapy isincreased by greater than about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,100%, 110%, 130%, 150%, 200%, 300%, 400%, or 500% in comparison toadministration of each mediation alone at an efficacious dose. In someembodiments, the specified period of time is from 1 to 8 weeks.

In a certain embodiment, the disclosure also provides thatadministration of an efficacious dose of a composition disclosed orcombined therapy disclosed herein to a subject with tinnitus whichresults in an improvement in the subject's tinnitus functional index, adecrease in the tinnitus loudness level in the subject, and/or adecrease in the number of days in which subject suffers from annoyingtinnitus.

The following examples are intended to illustrate but not limit thedisclosure. While they are typical of those that might be used, otherprocedures known to those skilled in the art may alternatively be used.

Examples

Subjects and Recruitment Method.

Adult subjects are recruited via a high-volume tertiary referral center.Subjects will be enrolled in the studies: if the subject (1) hasmoderate to severe (subjective severity) symptoms; (2) compliant withtheir mediations; (3) can attend study visits. After obtaining aninformed consent, the test subjects will undergo a comprehensive medicalhistory review and be physically examined. Any previous examinationtests, if applicable, will be obtained and evaluated pre-trial.Exclusion criteria will then be applied. Such exclusion criteria caninclude pregnancy, psychosis, definite Meniere's disease, neurologicalneoplasm, active external or middle ear disease, history ofendolymphatic sac surgery, history of allergic reaction to or adverseevents with the study medications, suffering from a medical condition orhaving a history that may be concerning to the investigators' clinicalopinion, and contraindications for the medications which preventsubjects from randomization.

General Study Design.

A randomized, double-blinded, placebo controlled, single institutional12-week trial will be performed. Subjects will be randomly assigned tothe experimental or control groups using a block randomizationtechnique. Both groups will receive instructions for dietary andlifestyle modifications to control for any potential confounding effectsdue to symptom triggers. The experimental group will receive theproposed combined medication regimen according to an algorithm withescalating doses as validated in preliminary retrospective studies.Escalating doses will continue until symptom improvement or until amaxim dose has been reached. If the subjects do not improve at themaximum dosage level; they will be considered to have failed medicationtherapy and will be tapered down to zero with gradual dosede-escalation. The subjects will visit a second time at week 8.

Subjects in the control group will receive a placebo that will besupplied in a similar size and shape to the experimental drugs. Thesesubjects will also follow similar escalation protocol. The pills will besupplied from the pharmacy with a unique identifier and the subjects'group will not be disclosed to the team prior to the end of the study.All subjects will be asked to report potential side effects. Thosereporting potential side effects will be seen and examined by medicalpractitioners to assess the safety of their continued enrollment and/orneed for additional treatment.

General Study Evaluations.

Following enrolment in the study, subjects will be followed over acourse of 8 weeks. Subjects will be seen twice, one pre-trial visit andone at the end of the 8^(th) week. Data regarding independent variablessuch as demographics, medical history, medications, imaging studies, andprevious treatments will be collected during the pre-trial visit.Primary outcomes will be evaluated. These measures will help determineadjustment of medication dosages. Subjects will additionally be asked tofill in surveys about their conditions and their symptoms at thepre-trial visit as well as post-trial (8^(th) week) visit.Accomplishment of the study aims will provide a pilot assessment of theeffectiveness of combined therapy in the treatment of condition and themedication's side effect profile.

Study design for the combined treatment of Tinnitus with ananticonvulsant and an antidepressant. A randomized, double-blinded,placebo controlled, single institutional 12-week study will be carriedout. Subjects will be randomly assigned to the experimental or controlgroups using a block randomization technique. Both groups will receiveinstructions for tinnitus dietary and lifestyle modifications to controlfor any potential confounding effects from tinnitus triggers. Theexperimental group will receive the proposed migraine medication regimenaccording to an algorithm with escalating doses that has been developedand validated in preliminary retrospective studies. The algorithm forthe experimental group is as follows: subjects in the experimental groupwill be started on a pill qhs (every bedtime) containing 7.5 mgnortriptyline plus 10 mg topiramate. They will receive a phone callevery week to gauge their response to the study drug (or placebo) basedon a visual analogue scale. On this weekly basis call, subjects will beinstructed to increase the dosage of medications (7.5 mg-step fornortriptyline plus 10 mg-step for topiramate) if tinnitus symptoms donot improve. This process will continue until they reach a maximum doseof 60 mg for nortriptyline and 80 mg for topiramate. If they do notimprove at this dosage level; they will be considered to have failedmedication therapy and will be tapered down to zero with gradual dosede-escalation. Subjects will be instructed to avoid increasing theirmedication dosage if their symptoms have improved. The subjects willvisit a second time at week 8.

Subjects in the control group will receive a placebo (MicrocrystallineCellulose; PH105) that will be supplied in a similar size and shape tothe experimental drug. These subjects will also follow similarescalation protocol as the PI and Co-PI will be blinded to therandomization. The pills will be supplied from the pharmacy with aunique identifier and the subjects' group will not be disclosed to theteam prior to the end of the study. The different dosage combinationsare made by the pharmacist in a single custom-made pill for thesubjects' conveniences. All subjects will be asked to report potentialside effects. Those reporting potential side effects will be seen andexamined by the Co-PI to assess the safety of their continued enrollmentand/or need for additional treatment.

Study Evaluations for Tinnitus.

Following enrolment in the study, subjects will be followed over acourse of 8 weeks. Subjects will be seen twice, one pre-trial visit andone at the end of the 8^(th) week. Data regarding independent variablessuch as demographics, medical history, medications, vestibular migrainerelated symptoms and clinical features, audiograms, imaging studies, andprevious treatments will be collected during the pre-trial visit.Primary outcomes will include the percentage of waking hours the subjectis aware of the tinnitus, minimum masking level (MML) and tinnitusloudness based on a visual analogue scale. Subjects' will additionallybe asked to fill in surveys about pre- and post-participation scores onTinnitus Functional Inventory (TFI), Perceived Stress Scale (PSS), andShort Form 12. The scores will be compared to evaluate for potentialchanges in the subject's condition. Secondary treatment outcomes fortinnitus will include changes in the tinnitus handicap. These measuresprovide a pilot assessment of the effectiveness ofnortriptyline-topiramate combination in the treatment of tinnitus andtheir side effect profile.

Tricyclic Antidepressant and Anti-Seizure Combination.

Nortriptyline Combined with Topiramate: 13 patients were treated withthe combination starting at a dose of 1 mg of nortriptyline and 7 mg oftopiramate. The dosages were gradually escalated up to 125 mg ofnortriptyline and 200 mg of topiramate. Of the 13 patients treated, 9had a substantial improvement in their tinnitus functional index andannoyance. The tinnitus loudness level decreased as well. The patientswith aural pressure/pain, fluctuating hearing loss, dizziness/vertigo,neck stiffness/headache, irritable bowel syndrome/interstitial cystitis,or fibromyalgia experienced an improvement in their symptoms.

Nortriptyline Combined with Gabapentin: 5 patients treated with thiscombination starting at a dose of 1 mg of nortriptyline and 40 mg ofgabapentin. The dosages were gradually escalated up to 125 mg ofnortriptyline and 2700 mg of gabapentin daily. Of the 5 patientstreated, 3 had a substantial improvement in their tinnitus functionalindex and annoyance. The tinnitus loudness level decreased as well.

Amitriptyline Combined with Topiramate: 4 patients were treated with thecombination starting at a dose of 1 mg of amitriptyline and 7 mg oftopiramate. The dosages were gradually escalated up to 125 mg ofnortriptyline and 200 mg of topiramate. Of the 4 patients treated, 3 hada substantial improvement in their tinnitus functional index andannoyance averaged over the previous week prior to presentation. Thetinnitus loudness level decreased as well.

Amitriptyline Combined with Gabapentin: 5 patients treated with thiscombination starting at a dose of 1 mg of amitriptyline and 40 mg ofgabapentin. The dosages were gradually escalated up to 125 mg ofamitriptyline and 2700 mg of gabapentin daily. Of the 5 patientstreated, 4 had a substantial improvement in their tinnitus functionalindex and annoyance. The tinnitus loudness level decreased as well.Average number of days with annoying tinnitus decreased.

Tricyclic Antidepressant and Beta Blocker Combination.

Nortriptyline Combined with Propranolol: 3 patients treated with thiscombination starting at a dose of 1 mg of nortriptyline and 9 mg ofpropranolol. The dosages were gradually escalated up to 125 mg ofnortriptyline and 160 mg of propranolol daily. Of the 3 patientstreated, 2 had a substantial improvement in their tinnitus functionalindex. Average number of days with very annoying tinnitus decreased.

Amitriptyline Combined with Propranolol: 3 patients treated with thiscombination starting at a dose of 1 mg of amitriptyline and 9 mg ofpropranolol. The dosages were gradually escalated up to 125 mg ofamitriptyline and 160 mg of propranolol daily. Of the 3 patientstreated, 2 had a substantial improvement in their tinnitus functionalindex.

Tricyclic Antidepressant and Calcium Channel Blocker Combination.

Nortriptyline Combined with Verapamil: 12 patients treated with thiscombination starting at a dose of 1 mg of nortriptyline and 20 mg ofverapamil. The dosages were gradually escalated up to 125 mg ofnortriptyline and 360 mg of verapamil daily. Of the 12 patients treated,9 had a substantial improvement in their tinnitus functional index.

Amitriptyline Combined with Verapamil: 3 patients treated with thiscombination starting at a dose of 1 mg of amitriptyline and 20 mg ofverapamil. The dosages were gradually escalated up to 125 mg ofamitriptyline and 360 mg of verapamil daily. Of the 3 patients treated,2 had a substantial improvement in their tinnitus functional index.

Tricyclic Antidepressant and Carbonic Anhydrase Inhibitor Combination.

Nortriptyline combined with acetazolamide: 5 patients treated with thiscombination starting at a dose of 1 mg of nortriptyline and 60 mg ofacetazolamide. The dosages were gradually escalated up to 125 mg ofnortriptyline and 1500 mg of acetazolamide daily. Of the 5 patientstreated, 3 had a substantial improvement in their tinnitus functionalindex.

Amitriptyline Combined with Acetazolamide: 3 patients treated with thiscombination starting at a dose of 1 mg of amitriptyline and 60 mg ofacetazolamide. The dosages were gradually escalated up to 125 mg ofamitriptyline and 1500 mg of acetazolamide daily. Of the 3 patientstreated, 2 had a substantial improvement in their tinnitus functionalindex.

Selective Serotonin Reuptake Inhibitor and Anti-Seizure Combination.

Paroxetine Combined with Topiramate: 8 patients were treated with thecombination starting at a dose of 3 mg of paroxetine and 7 mg oftopiramate. The dosages were gradually escalated up to 40 mg ofparoxetine and 200 mg of topiramate. Of the 8 patients treated, 6 had asubstantial improvement in their tinnitus functional index andannoyance. The tinnitus loudness level decreased as well. The patientswith aural pressure/pain, fluctuating hearing loss, dizziness/vertigo,neck stiffness/headache, irritable bowel syndrome/interstitial cystitis,or fibromyalgia experienced an improvement in their symptoms.

Paroxetine Combined with Gabapentin: 4 patients treated with thiscombination starting at a dose of 3 mg of paroxetine and 40 mg ofgabapentin. The dosages were gradually escalated up to 40 mg ofparoxetine and 2700 mg of gabapentin daily. Of the 4 patients treated, 2had a substantial improvement in their tinnitus functional index,loudness, and annoyance.

Selective serotonin reuptake inhibitor and beta blocker combination.

Paroxetine Combined with Propranolol: 4 patients treated with thiscombination starting at a dose of 3 mg of paroxetine and 9 mg ofpropranolol. The dosages were gradually escalated up to 40 mg ofparoxetine and 160 mg of propranolol daily. Of the 4 patients treated, 3had a substantial improvement in their tinnitus functional index.Average number of days with very annoying tinnitus decreased.

Selective Serotonin Reuptake Inhibitor and Calcium Channel BlockerCombination.

Paroxetine Combined with Verapamil: 7 patients treated with thiscombination starting at a dose of 3 mg of paroxetine and 20 mg ofverapamil. The dosages were gradually escalated up to 40 mg ofparoxetine and 360 mg of verapamil daily. Of the 7 patients treated, 5had a substantial improvement in their tinnitus functional index. Thepatients with aural pressure/pain, fluctuating hearing loss,dizziness/vertigo, neck stiffness/headache, irritable bowelsyndrome/interstitial cystitis, or fibromyalgia experienced animprovement in their symptoms.

Selective Serotonin Reuptake Inhibitor and Carbonic Anhydrase InhibitorCombination.

Paroxetine Combined with Acetazolamide: 4 patients treated with thiscombination starting at a dose of 3 mg of paroxetine and 60 mg ofacetazolamide. The dosages were gradually escalated up to 40 mg ofparoxetine and 1500 mg of acetazolamide daily. Of the 4 patientstreated, 2 had a substantial improvement in their tinnitus functionalindex.

Anti-Seizure and Calcium Channel Blocker Combination.

Verapamil Combined with Topiramate: 5 patients were treated with thecombination starting at a dose of 20 mg of verapamil and 7 mg oftopiramate. The dosages were gradually escalated up to 360 mg ofverapamil and 200 mg of topiramate. Of the 4 patients treated, 2 had asubstantial improvement in their tinnitus functional index and annoyanceaveraged over the previous week prior to presentation. The tinnitusloudness level decreased as well.

Verapamil Combined with Gabapentin: 6 patients treated with thiscombination starting at a dose of 20 mg of verapamil and 40 mg ofgabapentin. The dosages were gradually escalated up to 360 mg ofverapamil and 2700 mg of gabapentin daily. Of the 6 patients treated, 4had a substantial improvement in their tinnitus functional index andannoyance. The tinnitus loudness level decreased as well. Average numberof days with annoying tinnitus decreased.

Calcium Channel Blocker and Carbonic Anhydrase Inhibitor Combination.

Verapamil Combined with Acetazolamide: 4 patients treated with thiscombination starting at a dose of 20 mg of verapamil and 60 mg ofacetazolamide. The dosages were gradually escalated up to 360 mg ofverapamil and 1500 mg of acetazolamide daily. Of the 4 patients treated,3 had a substantial improvement in their tinnitus functional index.

It will be understood that various modifications may be made withoutdeparting from the spirit and scope of this disclosure. Accordingly,other embodiments are within the scope of the following claims.

What is claimed is:
 1. A composition for the treatment of an otologiccondition, or an otologic symptom(s) associated with a disease ordisorder, comprising therapeutically effective amounts of a firstmedication and a second medication selected from the following drugclasses: tricyclic antidepressants, anti-seizure medications, betablockers, carbonic anhydrase inhibitors, selective serotonin reuptakeinhibitors, and calcium or sodium channel blockers, wherein the firstmedication is from a different drug class than the second medication. 2.The composition of claim 1, wherein the first medication of thecomposition is a tricyclic antidepressant; and the second medication isselected from the group consisting of an anti-seizure medication, a betablocker, a calcium or sodium channel blocker, and a carbonic anhydraseinhibitor.
 3. The composition of claim 1, wherein the first medicationof the composition is a selective serotonin inhibitor; and the secondmedication of the composition is selected from the group consisting ofan anti-seizure medication, a beta blocker, a sodium or calcium channelblocker, and a carbonic anhydrase inhibitor.
 4. The composition of claim1, wherein the first medication is a calcium or sodium channel blocker;and the second medication is selected from the group consisting of atricyclic antidepressant, an anti-seizure medication, and a carbonicanhydrase inhibitor.
 5. The composition of claim 1, wherein the firstmedication of the composition is an anti-seizure medication; and thesecond medication of the composition is selected from the groupconsisting of a tricyclic antidepressant, a selective serotonininhibitor, a beta blocker, and a sodium or calcium channel blocker. 6.The composition of claim 1, wherein the first medication of thecomposition is a carbonic anhydrase inhibitor; and the second medicationof the composition is selected from the group consisting of a tricyclicantidepressant, a selective serotonin inhibitor, a and a sodium orcalcium channel blocker.
 7. The composition of claim 1, wherein thefirst medication of the composition is a beta blocker; and the secondmedication of the composition is selected from a tricyclicantidepressant and a selective serotonin reuptake inhibitor.
 8. Thecomposition of claim 1, wherein the first medication and the secondmedication combinations are selected from the group consisting ofnortriptyline and topiramate, nortriptyline and gabapentin,amitriptyline and topiramate, amitriptyline and gabapentin,nortriptyline and propranolol, amitriptyline and propranolol,nortriptyline and verapamil, amitriptyline and verapamil, nortriptylineand acetazolamide, amitriptyline and acetazolamide, paroxetine andtopiramate, paroxetine and gabapentin, paroxetine and propranolol,paroxetine and verapamil, paroxetine and acetazolamide, verapamil andtopiramate, verapamil and gabapentin, and verapamil and acetazolamide.9. The composition of claim 1, wherein the composition is formulated fororal delivery and is in the form of a pill, a tablet, or a capsule. 10.The composition of claim 1, wherein the composition comprises less thanabout 75% of the maximal dose of the first medication and/or the secondmedication.
 11. A method of treating an otologic condition, or anotologic symptom(s) associated with a disease or disorder, in a subjectin need thereof, comprising: administering to the subject a combinedtherapy comprising therapeutically effective amounts of two or moremedications selected from the following drug classes: tricyclicantidepressants, anti-seizure medications, beta blockers, carbonicanhydrase inhibitors, selective serotonin reuptake inhibitors, andcalcium or sodium channel blockers, wherein the two or more medicationsare from different drug classes.
 12. The method of claim 11, wherein theotologic condition is selected from the group consisting of tinnitus,fluctuating or sudden hearing loss, sensorineural hearing loss,dizziness, vertigo, aural pressure/pain, and fluctuating hearing loss,and wherein the otologic symptom(s) associated with a disease ordisorder comprises tinnitus and/or vertigo.
 13. The method of claim 11,wherein the subject is a human patient having tinnitus.
 14. The methodof claim 13, wherein administration of the combined therapy to thesubject provides one or more of the following effects: improvement in asubject's tinnitus functional index; a decrease in the average numberdays in which the subject has annoying tinnitus; and/or a decrease inthe level of tinnitus loudness.
 15. The method of claim 11, whereincombinations of the two or more medications of the combined therapy areselected from the group consisting of: a tricyclic antidepressant and ananti-seizure medication, a tricyclic antidepressant and a beta blocker,a tricyclic antidepressant and a sodium or calcium channel blocker, atricyclic antidepressant and a carbonic anhydrase inhibitor, a selectiveserotonin reuptake inhibitor and anti-seizure medication, a selectiveserotonin reuptake inhibitor and a beta blocker, a selective serotonininhibitor and a sodium or calcium channel blocker, an anti-seizuremedication and a sodium or calcium channel blocker, and a sodium orcalcium channel blocker and a carbonic anhydrase inhibitor.
 16. Themethod of claim 11, wherein the two or more medications of the combinedtherapy are selected from the group consisting of: nortriptyline,topiramate, amitriptyline, gabapentin, propranolol, verapamil,acetazolamide, and paroxetine.
 17. The method of claim 16, whereincombinations of the two or more medications of the combined therapy areselected from the group consisting of: nortriptyline and topiramate,nortriptyline and gabapentin, amitriptyline and topiramate,amitriptyline and gabapentin, nortriptyline and propranolol,amitriptyline and propranolol, nortriptyline and verapamil,amitriptyline and verapamil, nortriptyline and acetazolamide,amitriptyline and acetazolamide, paroxetine and topiramate, paroxetineand gabapentin, paroxetine and propranolol, paroxetine and verapamil,paroxetine and acetazolamide, verapamil and topiramate, verapamil andgabapentin, and verapamil and acetazolamide.
 18. The method of claim 11,wherein the two or more medications of the combined therapy areconcomitantly administered.
 19. The method of claim 11, wherein the twoor more medications of the combined therapy are sequentiallyadministered.
 20. The method of claim 11, wherein the two or moremedications of the combined therapy is administered at less than about75% of the maximal dose for the two or more medications.